Fatty liver is a pathological condition characterized by the accumulation of lipids, mainly neutral fat, within hepatocytes, and by hepatocyte steatosis seen in ⅓ or more of hepatic lobules. Among causes of fatty liver, those of importance are probably overconsumption of nutrition, obesity, overconsumption of alcohol, diabetes mellitus, total parenteral nutrition, some drugs, malnutrition, pregnancy, etc. Once the causes are eliminated, the pathological condition can be ameliorated and prognosis is good, but in some cases, fatty lever may be accompanied by inflammation and fibrosis, thus evolving to hepatic cirrhosis.
Nonalcoholic steatohepatitis (NASH) is a disease concept related to hepatic disorder observed in those taking no alcohol, and is a disease considered attributable to such as obesity, diabetes mellitus, hypertriglyceridemia, excessive nutrient uptake due to long-term parenteral nutrition, endocrine disorder, hypo-β-lipoproteinemia, and starvation/re-supplementation syndrome. NASH attracts attention since the number of patients with NASH has been increasing in recent years. NASH is a disease considered to be encountered relatively often even in a general practice, and many of the hepatitis that are not diagnosed as alcoholic liver disease, viral hepatitis or drug-induced hepatic injury are presumably categorized in this disease. Because there is histological similarity between alcoholic steatohepatitis and NASH, it is suggested that both of them have an analogous mechanism in pathogenesis, and the study of its details is still progressing at present.
In study of the pathogenic mechanism and prophylaxis/therapy of NASH, model animals showing the symptoms of NASH are necessary. Conventionally, ob/ob mice showing obesity, fatty liver and hyperinsulinemia attributable to deficiency of leptin gene are used as model animals of fatty liver, and rats fed choline/methionine-deficient diet are used as model animals of NASH, but these model animals do not fully reproduce human NASH because their livers are those of nonhuman animal origin.
Here, JP-A 2002-45087 discloses that a uPA transgenic mouse (uPA-Tg mouse), a genetically hepatopathic mouse in which a urokinase plasminogen activator (uPA) gene ligated to an enhancer/promoter for albumin produced in the liver has been introduced into all cells, is crossed with a SCID mouse, which is an immunodeficient mouse, thereby producing a uPA/SCID mouse, i.e., an immunodeficient hepatopathic mouse. Then, human hepatocytes are transplanted into this mouse, whereby a human hepatocyte chimeric mouse in which a part of the mouse liver has been replaced by human hepatocytes can be obtained.
Further, WO 03/080821 A1 discloses that human hepatocytes are transplanted into, and simultaneously a complement inhibitor is administered to, the above uPA/SCID mouse, whereby the replacement index of human hepatocytes in the liver of the mouse can be improved.